Risk Factors for Idiosyncratic Drug-Induced Liver Injury

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…Many risk factors predispose epileptic patients to idiosyncratic drug-induced mitochondrial dysfunction [155, 181, 182]. These risk factors are typically drug-specific and determination of clinical manifestations for diagnosis and prognosis of hepatotoxicity in a particular patient is difficult [183].…”

“…These risk factors are typically drug-specific and determination of clinical manifestations for diagnosis and prognosis of hepatotoxicity in a particular patient is difficult [183]. Yet, it is well documented that complex interactions between genetic and metabolic risk factors contribute to mitochondrial dysfunction in drug-induced liver injury [182]. The paramount concern is that mitochondrial disease and identification of mutations in the DNA polymerase-gamma gene are associated with mtDNA depletion/deletion and mitochondrial oxidative phosphorylation disease [149, 156].…”

Hepatobiliary Quiz (Answers)—16 (2015)

“…58 Age is a risk factor for specific drugs. 59 Children generally have a lower risk for DILI except from aspirin used during viral illnesses and valproate. [60][61][62] Women do not seem to be at an increased overall risk for DILI, however, they are more likely to progress to acute liver failure.…”

“…[60][61][62] Women do not seem to be at an increased overall risk for DILI, however, they are more likely to progress to acute liver failure. 59,63,55 10. Correct Answers: B and E Amoxicillin-clavulanate is the most frequent cause of idiosyncratic DILI in several European and American series.…”

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

“…Potential genetic risk factors and biomarkers, including micro-RNA, are presently being investigated to explain DILI and HILI disease [18][19][20] . These data provide promising clinical and scientific results but currently contribute little to diagnose DILI or HILI correctly and in time, or to exclude alternative causes.…”